Devices and methods for treating defects in the tissue of a living being

ABSTRACT

An implant for deployment in select locations or select tissue for regeneration of tissue is disclosed. The implant includes collagen and or other bio-resorbable materials, where the implant may also be used for therapy delivery. Additionally, the implant may be “matched” to provide the implant with similar physical and/or chemical properties as the host tissue.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the effective filing date of U.S. patentapplication Ser. No. 11/925,864, filed Oct. 27, 2007, now U.S. Pat. No.7,887,598, which is a continuation of U.S. patent application Ser. No.11/775,672, filed Jul. 10, 2007, which is a continuation of U.S. patentapplication Ser. No. 10/631,431, filed Jul. 31, 2003, now U.S. Pat. No.7,241,316, which is a continuation of U.S. patent application Ser. No.10/171,248, filed Jun. 13, 2002, now U.S. Pat. No. 7,166,133, which areassigned to the same assignee as this invention and whose disclosuresare fully incorporated by reference herein. This application claimssubject matter which was previously subject to restriction, withdrawnand cancelled. Thus this application is a divisional application.

BACKGROUND OF THE INVENTION

This invention relates generally to medical devices and procedures andmore particularly to devices and methods for treating defects in thetissue of a living being.

To better treat our aging population, physicians are looking for new andbetter products and methods to enhance the body's own mechanism toproduce rapid healing of musculoskeletal injuries and degenerativediseases. Treatment of these defects has traditionally relied upon thenatural ability of these types of tissue to repair themselves. In manyinstances the body is unable to repair such defects in a reasonabletime, if at all. Advances in biomaterials has allowed for the creationof devices to facilitate wound healing in both bone and soft tissuesdefects and injuries. Such devices are used in tissue regeneration astissue (e.g. bone) graft scaffolds, for use in trauma and spinalapplications, and for the delivery of drugs and growth factors.

Bone and soft tissue repair is necessary to treat a variety of medical(e.g. orthopedic) conditions. For example, when hard tissue such as boneis damaged as a result of disease or injury, it is often necessary toprovide an implant or graft to augment the damaged bone during thehealing process to prevent further damage and stimulate repair. Suchimplants may take many forms (e.g. plugs, putties, rods, dowels, wedges,screws, plates, etc.) which are placed into the tissue. Typically, suchimplants can be rigid, flexible, deformable, or flowable and can beprepared in a variety of shapes and sizes. For rigid implants (e.g. bonescrews), the defect site is typically preconditioned by forming adepression, channel, or other feature (e.g. pre-tapped hole) therein inpreparation for the application of the implant. For non-rigid structuralrepair materials (e.g. putties and pastes) to be conveniently used, theymust be capable of being formed into a variety of complex shapes to fitthe contours of the repair site. An accurately configured implant thatsubstantially fills the defect site will enhance the integration ofnatural bone and tissue to provide better healing over time. Forexample, when repairing defects in bone, intimate load carrying contactoften is desired between the natural bone and the bone substitutematerial to promote bone remodeling and regeneration leading toincorporation of the graft by host bone.

Current bone graft materials include autografts (the use of bone fromthe patient), allografts (the use of cadaver bone), and a variety ofother artificial or synthetic bone substitute materials. Autografts aretypically comprised of cancellous bone and/or cortical bone. Cancellousbone grafts essentially provide minimal structural integrity. Bonestrength increases as the implant incorporates surrounding cells and newbone is deposited. For cortical bone, the graft initially provides somestructural strength. However, as the graft is incorporated by the hostbone, nonviable bone is removed by resorption significantly reducing thestrength of the graft. The use of autograft bone may result in severepatient pain and other complications at the harvest site, and there arelimitations to the amount of autograft bone that can be harvested fromthe patient. Allografts are similar to autografts in that they arecomprised of cancellous and/or cortical bone with greater quantities andsizes being typically available. Disadvantages of allografts includelimited supplies of materials and the potential for transmission ofdisease. The disadvantages of the existing products creates a need for abetter devices and methods for treating defects in the tissue of aliving being.

Collagen is the most abundant protein found in the body. The uniquechemistry of collagen makes it an ideal material for structural andhemostatic applications in both clinical and diagnostic settings.Collagen, like all proteins, is comprised of amino acids linkedcovalently through peptide or amide linkages. The sequence of the aminoacids, or the primary structure, outlines the three-dimensionalstructure of the protein which in turn dictates the function andproperties of the molecule. Collagen is composed of three peptide chainsassociated in a triple helical orientation. These triple helicesassociate to form fibrils which ultimately make up connective tissue andother structural member.

Collagen has been used in a number of applications in the art. Forexample, one application is for use in hemostatic devices for thestoppage of bleeding, such as is described in U.S. Pat. Nos. 5,310,407(Casal) and 4,890,612 (Kensey). However, neither teaches the use ofnative insoluble fibrous collagen. In U.S. Pat. No. 5,425,769, Snyders,Jr. discloses a biocompatible and bioresorbable bone substitute withphysical and chemical properties similar to bone, consisting ofreconstituted fibrillar collagen within a calcium sulfate di-hydratematrix. The ratios of calcium sulfate and collagen are adjusted for eachapplication and the bone substitute is molded in situ to form a solidphase. Similarly, U.S. Pat. No. 5,425,770 (Piez, et. al.) discloses acomposition made from a calcium phosphate particulate mineral such ashydroxyapatite or tricalcium phosphate mixed with atelopeptidereconstituted fibrillar collagen for conductive bone repair. U.S. Pat.No. 5,904,718, (Jefferies) describes a process and invention comprisingdemineralized bone particles and collagen. Examples of medical implantsthat utilize reconstituted fibrous collagen include U.S. Pat. Nos.4,642,117 (Nguyen™, et al.), 4,795,467 (Piez, et al.), and 5,997,896(Carr, et al.). The '718, '769 and '770 patents, all require the use ofreconstituted collagen.

U.S. Pat. Nos. 4,563,350 and 4,888,366 describe the use of lyophilizedand preformed collagen carriers of osteoinductive factors in bonerepair, respectively. When used as preformed solid implants, thesecarriers consist generally of ceramic materials which are held togetherby collagen. Similarly, U.S. Pat. No. 4,776,890 describesnon-crosslinked collagen/mineral implants, which can be moistened andmolded into a desired shape before implantation. Therein, crosslinkingis described as being undesirable because of its inhibitory effects onbone in-growth. U.S. Pat. Nos. 4,795,467, 5,035,715 and 5,110,604describe porous collagen-containing implants for use in bone repairand/or wound healing. U.S. Pat. No. 4,948,540 (Nigam) describes a typeof fibrous native collagen for use as a hemostatic dressing. Thesereferences do not teach or suggest the solution to the ubiquitousproblem of high porosity and excessive resilience in acollagen-containing implant material for bone defect repair.

Devices made from compressed collagen matrices include Robinson et al.(Cardiovasc Intervent Radiol 1990; 13:36-39), who described the use ofcompressed collagen plugs prepared from Gelfoam™ (manufactured byPharmacia & Upjohn Company, Kalamazoo, Mich.) to repair biopsy tractdefects in lungs. Armstrong et al. (Arch Dermatol 1986; 122:546-549)described the use of compressed collagen plugs prepared from Helistat™(manufactured by Integra LifeSciences) to repair cutaneous biopsywounds. All of these references teach the use of collagen but none teachthe use of the multi-phasic composition of the present invention,furthermore the function of these devices is for stopping the bleedingfrom a puncture and not for regenerating tissue.

Accordingly, a need remains for a defect filling material, preparedprimarily of collagen, which has improved mechanical stability and isadequately dense and sufficiently conformable for medical or surgicalutility.

U.S. Pat. No. 6,110,484 (Sierra) describes an implant formed in situ,that contains a biodegradable porosifying agent; however the embodimentis a pre-formed solid plug and porosity is not rapidly created followingimplanting, to form an osteoconductive structure. Therefore, a needexists for an implant that rapidly becomes porous followingimplantation.

Various embodiments of these devices include polysaccharides in theconstruct. Polysaccharides are a key component of the extracellularmatrix component of bone and related tissue, since they providehydrophilicity and important structural aspects. When incorporated intomedical implants, polysaccharides also impart hydrophilicity and help toregulate the wound healing response associated with the implant, as wellas improve cell attachment. The combination of Polysaccharides andcollagen has been described by U.S. Pat. Nos. 4,614,794 (Easton, et.al.) and 5,972,385 (Liu, et.al.). '794 is limited to fabrication from ahydrolytic degradation process, and the '385 device must be crosslinked.Therefore, a need exists for a polysaccharide that is not limited tofabrication from a hydrolytic degradation process, and the that does notrequire cross-linking.

Demineralized bone alone may be useful for repair of bony defects, thereis much inconsistency because bone is a natural material. Someapproaches to harvesting these minerals include defatting, grinding, andcalcining or heating the bone. However, the resulting mixture of naturalbone mineral is chemically and physically variable. Additionally,allogenic bone from cadavers must be harvested carefully under rigidconditions and then properly stored in tissue banks to prevent possibleimmunologic complications or possible transmission of viral or bacterialpathogens. Sterilization of demineralized bone may alter thephysiochemical properties critical for bone induction when methods suchas gamma radiation employed. It is recognized that irradiation ofdemineralized bone powder before implantation weakens the osteogenicresponse by approximately 20%. It is therefore extremely difficult touse natural bone as an implant, thus there remains a need for asynthetic bone replacement material.

In U.S. Pat. No. 5,425,769, (Snyders, Jr., et al.) teaches that therehave been many attempts to enhance the handling and osteogenic abilityof calcium phosphate implants by incorporation of calcium phosphategranules into a binding matrix such as plaster of Paris or soluble orreconstituted fibrous collagen. This will improve the workability of theimplant and encourage bony in-growth through partial resorption of theimplant. Disadvantages of this conjugate include the inability of themalleable collagen matrix to attain a solid state in vivo and theresistance of solidifying plaster matrices to molding. The is overcomeby the present invention with a unique blend of soluble and nativefibrous collagen which maintains its strength following implantation,while still remaining somewhat compliant, without the need for ceramicadditives; although, the present invention contemplates the potentialimprovement of their use.

In U.S. Pat. No. 4,394,370, Jefferies describes an implant made ofreconstituted collagen and either demineralized bone or else bonemorphogenic protein, and which when implanted into bone, will causeosteogenesis. The collagen may be chemically cross-linked. The physicalproperties of these sponges is not specified in the disclosure, however,reports of the handling of similar collagen sponges indicates thesematerials to be very weak and quickly resorbable (no wet tear strengthand resorption in 1 to 2 weeks).

Additionally, in U.S. Pat. No. 4,430,760, Smestad describes an implantconsisting of demineralized bone or dentin inside of a container madefrom either fibers such as collagen or a microporous membrane. The poresof the implant are sized so that it selectively allows osteocytes andmesenchymal cells to pass, but does not allow the particulatedemineralized bone or dentin to pass through. The problem concerningthis patent is that it can not be used in load-bearing locations.Therefore, a need exists for an implant that will maintain structural ormechanical integrity following implant.

In U.S. Pat. No. 4,440,750, Glowacki et al. describe an aqueousdispersion of reconstituted collagen fibers mixed with demineralizedbone particles for use in inducing bone formation. This graft materialpossesses little physical strength and mechanical properties and thus,its uses are limited. Furthermore, with time, the demineralized boneparticle suspended within the aqueous collagen sol-gel begin to settleunder gravitational forces, thus producing an non-homogeneous orstratified graft material; whereas the present invention providesstrength, and does not utilize sol-gel processing thereby avoiding anysettling of gel constituents, or other unintentional non-homogeneity.Additionally, U.S. Pat. No. 4,485,097 (Bell) describes a materialcomposed of a hydrated collagen lattice, fibroblast cells, anddemineralized bone powder. This material is in the form of a hydratedcollagen gel, and therefore has minimal physical strength or mechanicalintegrity. Therefore, the material fails to meet the aforementionedshortcomings in the art.

In U.S. Pat. No. 4,623,553, Ries et. al. describes a method forproducing a bone substitute material consisting of collagen andhydroxyapatite and partially crosslinked with a suitable crosslinkingagent, such as glutaraldehyde or formaldehyde. The order of addition ofthese agents is such that the crosslinking agent is added to the aqueouscollagen dispersion prior to the addition of the hydroxyapatite orcalcium phosphate particulate material. The resultant dispersion ismixed and lyophilized. The '553 patent lacks any components which areknown osteogenic inducers, such as demineralized bone matrix orextracted bone proteins. Similarly, U.S. Pat. Nos. 4,865,602 and5,035,715, (Smestad, et. al.) describe a process for preparing abiocompatible bone implant composed of atelopeptide fibrillarreconstituted collagen and a mineral component which may be calciumphosphate, hydroxyapatite, or tricalcium phosphate. The implant is gammasterilized with enough irradiation to cause cross-linking of thecollagen in order to produce the desired handling and mechanicalproperties for the implant. The '602, '715, and '553 patents differ fromthe present invention in that they require crosslinking, which issuspected to be detrimental to in-growth, additionally, the '602 and'715 patents include a reconstituted collagen matrix.

In U.S. Pat. No. 5,071,436 Huc et. al. describe a new bone-substitutebiomaterial which is a combination of collagen, hydroxyapatite, andglycosaminoglycans and in the form of a sponge. The concentration of theglycosaminoglycans is preferably between 1 and 2% per liter of 1%collagen gel. The concentration of the hydroxyapatite and the collagento each other is preferably about equal, which is six times greater thanthe concentration of glycosaminoglycan component.

In U.S. Pat. No. 5,320,844, Liu et. al. describes a composite materialfor hard tissue replacement whose properties are similar to naturalbone. The synthetically derived, homogenous composite contains acollagen component and a calcium phosphate-containing componentprecipitated from a liquid medium.

In U.S. Pat. No. 5,711,957, Patat et al. discloses an implant made of aporous calcium carbonate-based material as an external wall to support agrowth factor. These authors also teach why they believe that thepresence of collagen is neither necessary nor desirable in the case whenthe implant is intended to be used as a bone-formation implant,regardless the external wall of '957 is the only region housing a growthfactor.

In U.S. Pat. No. 5,904,718, Jefferies describes a chemicallycross-linked matrix of demineralized bone particles or collagen whichmay or may not contain a drug or mineral additive. The 718 patentdiscloses that the cross-linking enables the construct to have amechanical strength. Further, the 718 patent discloses that thecross-linking can conjugate the drug or mineral to the organic matrix.Embodiments of the current invention do not rely on crosslinking forstrength, nor does it rely on crosslinking for conjugation of drugs orother therapies; this is an important feature of the present invention,since crosslinking has been shown by others to inhibit tissue ingrowth.

The fabrication of and application of microspheres is known and as suchthe following examples are included herein as reference. U.S. Pat. No.3,887,699 describes a solid biodegradable polymer spheroid implantswhich incorporate a drug for sustained release as the polymer naturallydegrades in the human body. Many different methods of constructing thistype of controlled release system have been developed. Although theuniform matrix of a polymer provides a simple and efficient structurefor the controlled release of agents with microspheres, many advancedmethods of containing and releasing the therapeutic agents have beendeveloped. U.S. Pat. No. 4,637,905 (Gardner) discloses a method forencapsulating a therapeutic agent within a biodegradable polymermicrosphere. U.S. Pat. No. 4,652,441 (Okada et al.) discloses a methodof utilizing a water-in-oil emulsion to give prolonged release of awater-soluble drug. The patent describes a wide variety of drugs thatcan be delivered via prolonged release micro-capsules as well assuitable polymeric materials and drug retaining substances. It isconceived that the system of this invention could incorporate any of thedrugs described to in this patent to generate a beneficial effect in thecardiac tissue. U.S. Pat. No. 5,718,921 (Mathiowitz et al.) discloses amethod for constructing a multiple layer microsphere which can releasetwo different drugs at controlled rates or a singe drug at two differentrates. U.S. Pat. No. 5,912,017 (Mathiowitz et al.) also discloses amethod of forming two layered microspheres by using an organic solventor melting two different polymers, combining them with a desiredsubstance and cooling. Microspheres are not limited to justwater-soluble therapeutic agents. See, for example, U.S. Pat. No.5,288,502 (McGinity et al.) which discloses a multi-phase microspherewhich is capable of incorporating water-soluble and water-insolubledrugs.

SUMMARY OF THE INVENTION

This invention includes various aspects. For example there is provided asystem and method for treating tissue within the body of a living being.The current invention essentially comprises a synthetic tissuesubstitute material and a method and system for deploying the implant.Some of the significant advantages and features of the variousembodiments of the present invention include, but are not limited to,the following characteristics:

-   1) It is an object of the present invention to provide an implant    that is generally fabricated from one or more biocompatible    materials that will act as a scaffold for the in-growth of tissue.    Example materials include polymers (e.g. polyesters, collagen,    polysaccharides), ceramics, and metals;-   2) It is an object of the present invention to provide an implant    that can contain a material that maintains the required level of    physical integrity after implantation;-   3) It is an object of the present invention to provide an implant    wherein, at least a portion of, if not all of, the device when    implanted will resorb after it is no longer needed;-   4) It is an object of the present invention to provide an implant    that serves to restore the mechanical, architectural and structural    competence to the tissue defect or bone void being treated;-   5) It is an object of the present invention to provide an implant    that contains a depot of material (e.g. calcium salts, collagens,    cytokines, drugs, etc.) for assisting the in-growth of cells;-   6) It is an object of the present invention to provide an implant    that may provide a biologically acceptable and mechanically stable    surface structure suitable for genesis, growth and development of    new connective tissue (e.g., non-calcified, calcified);-   7) It is an object of the present invention to provide an implant    that can act as a carrier for the other constituents of the    invention which do not have mechanical and structural competence    (e.g. soluble collagen, drugs, biologics, cells, etc.);-   8) It is an object of the present invention to provide an implant    that can act as a carrier for the other constituents of the    invention which act to beneficially treat the living being in which    they are implanted (e.g. drugs, biologics, cells, radioisotopes,    platelet rich plasma, etc.);-   9) It is an object of the present invention to provide an implant    that can, when used for bone applications, and certain other    applications as are described herein, the implant provides an    osteoconductive matrix providing a scaffold for bone in-growth.-   10) It is an object of the present invention to provide an implant    that can incorporate osteoinductive factors providing chemical    agents that induce bone regeneration and repair.-   11) It is an object of the present invention to provide an implant    that can incorporate osteogenic cells for providing the basic    building blocks for bone regeneration by their ability to    differentiate into osteoblasts and osteoclasts.-   12) It is an object of the present invention to provide an implant    that can also provide structural integrity to the defect and    surrounding tissues to a level that is suitable for some load to be    carried by the implant.-   13) It is an object of the present invention to provide an implant    that can provide a biocompatible alternative for utilizing    autologous bone (e.g. from the illiac crest or rib) or other tissue    for grafting purposes;-   14) It is an object of the present invention to provide an implant    that can create an environment which is conducive to tissue    regeneration (e.g. osteogenesis) in its own right;-   15) It is an object of the present invention to provide an implant    that can function as a carrier for biologically active agents (i.e.    chemotactic substances) or other osteoinductive/osteogenic agents,    as well as other therapeutic substances (i.e. antibiotics);-   16) It is an object of the present invention to provide an implant    that can resorb or degrade (at least partially) in several stages to    allow for new tissue in-growth and to eliminate the need for second    surgeries to remove the implant; and,-   17) It is an object of the present invention to provide an implant    that can utilize native fibrous collagen to provide structural    integrity to the implant and serves as an ideal substrate for tissue    regeneration.

To that end, a preferred embodiment of the treatment system comprises adelivery instrument and an implant. The implant may comprise one or morebiocompatible materials for introduction into the bone or other tissueto be treated. The delivery instrument is arranged to introduce theimplant at or adjacent to the targeted tissue, whereupon the implantdirectly enters the targeted tissue at an entry situs.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates in plan view the tissue treatment system 10 of thepresent invention, partly cut away to show in cross-section itsconstituent components, including a sheath, an applicator plunger and apreloaded implant disposed within the sheath.

FIG. 2A is a perspective view of one embodiment of the implant of thesubject invention.

FIG. 2B is a perspective view of an alternative embodiment of theimplant of the subject invention.

FIG. 2C is a perspective view of an alternative embodiment of theimplant.

FIG. 2D is a perspective view of an alternative embodiment of theimplant.

FIG. 2E is a perspective view of an alternative embodiment of theimplant.

FIG. 2F is a perspective view of an alternative embodiment of theimplant.

FIG. 2G is a perspective view of an alternative embodiment of theimplant.

FIG. 2H is a perspective view of an alternative embodiment of theimplant.

FIG. 3 is a perspective view of an alternative embodiment of theimplant.

FIG. 4 is a perspective view of one of the various types of tissue thatis suitable for treatment by the treatment system of the subjectinvention.

FIG. 5 is a cross-sectional view of tissue from FIG. 4, in partial view,and enlarged.

FIG. 6 is an enlarged detailed perspective view of a portion of thetissue shown in FIG. 4.

FIG. 7 illustrates in plan view a tissue treatment system of the presentinvention, partly cut away to show in cross-section its constituentcomponents, delivering an implant into tissue of a living being.

FIG. 8 illustrates in plan view a tissue treatment system of the presentinvention, partly cut away to show, in cross-section its constituentcomponents, being removed from the tissue after delivering an implantinto the tissue of a living being.

FIG. 9 illustrates a cross-sectional view of the treated tissue,containing an implant, and an instrument for contouring the implant.

FIG. 10 is a side elevational view of an alternate treatment anddelivery system 110 of the subject invention.

FIG. 11 illustrates a side elevational view of a tissue treatment system110 of the present invention, modifying the tissue of the living being.

FIG. 12 illustrates a side elevational view of the tissue treatmentsystem 110 of the present invention, shown removing a core of tissuefrom a living being.

FIG. 13 illustrates a side elevational view partially in section of atissue treatment system 110 of the present invention, delivering animplant into tissue of a living being.

FIG. 14 is a side view in partial cross-section of a portion of oneembodiment of the treatment system of the subject invention shown priorto loading of the implant material into the system.

FIG. 15 is a side view in partial cross-section of a portion of oneembodiment of the treatment system of the subject invention shown withan implant loaded within the system.

FIG. 16 is a side view in partial cross-section of a portion of oneembodiment of the treatment system of the subject invention shown withan implant loaded and being advanced within the treatment system.

FIG. 17 is a plan view of yet another embodiment of the tissue treatmentsystem 200 of the present invention, partly cut away to show incross-section its constituent components, including a sheath, anapplicator plunger.

FIG. 18 is a plan view of the tissue treatment system 200 shown in FIG.17 assembled to an implant carrying device 202.

FIG. 19 is a plan view of the tissue treatment system 200 shown in FIG.17 assembled to another embodiment of an implant carrying device 204.

FIG. 20 is a side sectional view of the implant carrying devices shownin FIG. 18 and FIG. 19.

FIG. 21 is a perspective view of the implant carrying devices shown inFIGS. 18-20.

FIG. 22 depicts a 100× Scanning Electron Microscope image of a bonereplacement material. This implant is composed of Kensey Nash P1076, abovine hide-derived collagen material that is a combination of nativecollagen fibers and soluble collagen. The pores comprising themacrostructure of the implant are between 100-um and 200-um in diameter.

FIG. 23 depicts a 100× Scanning Electron Microscope image of a bonereplacement material. A constituent of this implant is Kensey NashP1076, a bovine hide-derived collagen material that is a combination ofnative collagen fibers and soluble collagen. Blended into the collagenat 25% by weight is medical grade calcium sulfate, shown as the smallcylindrical particles throughout the porous macrostructure.

FIG. 24 depicts a 100× Scanning Electron Microscope image of a bonereplacement material. This implant is composed of Kensey Nash P1076, abovine hide-derived collagen material that is a combination of nativecollagen fibers and soluble collagen. This implant has been crushed byapproximately 233% causing the pore size to decrease to 20-um to 50-um.

FIG. 25 is a cross-sectional view of tissue containing an embodiment ofthe implant of the subject invention that releases and agent to treatsthe local tissue.

FIG. 26 is a cross-sectional view of a tissue containing an embodimentof the implant of the subject invention showing the gradual resorptionof the implant and tissue regeneration occurring over time.

FIG. 27 is a cross-sectional close-up view of one embodiment of theimplant material of the subject invention.

FIG. 28. is a perspective view of an alternative embodiment of theimplant 240 of the subject invention.

FIG. 29 is a side view in partial cross-section of an embodiment of anagent delivery system loading an implant with an agent.

FIG. 30 is a side view in partial cross-section of a portion of adelivery system applying yet another embodiment of an implant of thesubject invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

A preferred embodiment of current invention essentially consists of animplant comprising a tissue (e.g., bone, cartilage, soft tissue, etc.)substitute material and a method and system for deploying the implant.In general the implant of this invention is generally fabricated fromone or more biocompatible materials (e.g. polymer, metal, ceramic) thatwill act to treat the wound and serve as a scaffold for the in-growth oftissue. The implant may contain a depot of material (e.g. calcium salts,collagens, cytokines, drugs, etc.) for assisting the in-growth of cellsand act as a carrier for other constituents (e.g., see tables 2 through7, and accompanying discussion, etc.) of the invention which act tobeneficially treat the living being in which they are implanted. Someembodiments of the invention also incorporate cells or other biologicalconstituents for providing the basic building blocks for tissueregeneration.

Many materials can be used to construct the implant, or a portionthereof, of our invention. Biocompatible polymers (e.g., collagen,chitosan, alginate, polylactide-co-glycolide, polyurethane,polyethylene) are preferred for use in this invention. As will bedescribed later, collagen, and most specifically native fibrouscollagen, is a preferred constituent of the implant. Additionally,biocompatible resorbable synthetic polymers may be used, such as, butnot limited to, those listed in table 1. However, virtually anybiodegradable and/or biocompatible material may be used with the presentinvention.

In the art, there exists three general classes of collagen that aretypically useful as medical implant materials. These includecollagen-based implants comprised of soluble collagen, reconstitutedcollagen fibers, or natural insoluble collagen fibers.

First, “Soluble collagen” refers to the solubility of individualtropocollagen molecules in acidic aqueous environments. Tropocollagenmay be considered the monomeric unit of collagen fibers and its triplehelix structure is well recognized.

Second, “reconstituted collagen” is essentially collagen fiber segmentsthat have been depolymerized into individual triple helical molecules,then exposed to solution and then re-assembled into fibril-like forms.Therefore, the degree of polymerization of reconstituted collagen isbetween that of soluble and native insoluble fibrous collagen. Adisadvantage of reconstituted collagen is, in general, the mechanicalstrength and in vivo persistence are inferior to native (i.e. natural)insoluble fibrous collagen.

Third, “Natural insoluble collagen” as used herein means and refers tocollagen that cannot be dissolved in an aqueous alkaline or in anyinorganic salt solution without chemical modification, and includes forexample hides, splits and other mammalian or reptilian coverings. Forexample, “natural insoluble collagen” can be derived from the corium,which is the intermediate layer of a animal hide (e.g. bovine, porcine,etc.) that is situated between the grain and the flesh sides.

In this embodiment, as well as the balance of the specification andclaims, the term “bioabsorbable” is frequently used. There exists somediscussion among those skilled in the art, as to the precise meaning andfunction of bioabsorbable material (e.g., polymers), and how they differfrom resorbable, absorbable, bioresorbable, biodegradable, andbioerodable. The current disclosure contemplates all of these materials,and combines them all as bioresorbable; any use of an alternatedisclosed in this specification is meant to be inclusive of the others.

TABLE 1 Examples of Additional Biodegradable Polymers for Use inConstruction of the Matrix of this Invention Aliphatic polyestersCellulose Chitin Collagen Copolymers of glycolide Copolymers of lactideElastin Fibrin Glycolide/l-lactide copolymers (PGA/PLLA)Glycolide/trimethylene carbonate copolymers (PGA/TMC) HydrogelLactide/tetramethylglycolide copolymers Lactide/trimethylene carbonatecopolymers Lactide/ε-caprolactone copolymers Lactide/σ-valerolactonecopolymers L-lactide/dl-lactide copolymers Methyl methacrylate-N-vinylpyrrolidone copolymers Modified proteins Nylon-2 PHBA/γ-hydroxyvaleratecopolymers (PHBA/HVA) PLA/polyethylene oxide copolymers PLA-polyethyleneoxide (PELA) Poly (amino acids) Poly (trimethylene carbonates) Polyhydroxyalkanoate polymers (PHA) Poly(alklyene oxalates) Poly(butylenediglycolate) Poly(hydroxy butyrate) (PHB) Poly(n-vinyl pyrrolidone)Poly(ortho esters) Polyalkyl-2-cyanoacrylates PolyanhydridesPolycyanoacrylates Polydepsipeptides Polydihydropyrans Poly-dl-lactide(PDLLA) Polyesteramides Polyesters of oxalic acid Polyglycolide (PGA)Polyiminocarbonates Polylactides (PLA) Poly-l-lactide (PLLA)Polyorthoesters Poly-p-dioxanone (PDO) Polypeptides PolyphosphazenesPolysaccharides Polyurethanes (PU) Polyvinyl alcohol (PVA)Poly-β-hydroxypropionate (PHPA) Poly-β-hydroxybutyrate (PBA)Poly-σ-valerolactone Poly-β-alkanoic acids Poly-β-malic acid (PMLA)Poly-ε-caprolactone (PCL) Pseudo-Poly(Amino Acids) Starch Trimethylenecarbonate (TMC) Tyrosine based polymers

As described previously, one of the preferred constituent materials ofthe device is collagen, or more specifically native fibrous collagen.One embodiment of the present invention combines two or more forms ofcollagen to create a unique composite material with multi-phasicproperties. A mechanically stable, conformable collagen-based implant isfabricated by lyophilizing (freeze-drying) a specialized collagensuspension of native insoluble collagen fibers suspended in a solublecollagen slurry of desirable viscosity. In the preferred embodiment theratio of soluble to insoluble fibrous collagen is maintained in therange of about 1:20 to 10:1, and the resulting product is compressed toa volume between about 5 and 95 percent of its starting volume. However,other ratios of constituent materials or compressive levels can beutilized depending upon the desired result. The material may be treatedwith optional physical crosslinking techniques (e.g. dehydrothermal,gamma radiation, ethylene oxide, or ultraviolet radiation) known in theart. Chemical crosslinking methods can be utilized where the addition ofchemical crosslinking agents, whose residual elements may inhibit thehealing process, does not produce deleterious effects. Implants preparedin such a fashion demonstrate high absorptivity, i.e., about 5-20 timesits weight in isotonic saline, making it highly useful as a carrier forother agents (e.g., drugs, biologics, cells, etc.). The implant may thenbe coated, impregnated or combined with a variety of other materials toenhance mechanical or healing properties.

Because the collagen suspension of the preferred embodiment of thepresent invention contains both soluble and insoluble collagen, thesoluble collagen and insoluble collagen fibers are first preparedseparately, then combined. Both the soluble collagen and the naturalinsoluble collagen fibers (“native collagen fibers”) in accordance withthe present invention are preferably derived from bovine hides but canbe prepared from other collagen sources (e.g. bovine tendon, porcinetissues, recombinant DNA techniques, fermentation, etc.).

To create a multi-phasic implant for example, the soluble and fibrouscollagen can be lyophilized and subsequently optionally crosslinked toproduce a mechanically stable and porous collagen structure. Compressionof the collagen sheet renders the construct less porous and effectivelyincreases the density of the implant. When implanted, the solublecollagen will degrade faster than the native fibrous collagen. Thesoluble collagen will thus act like a delayed “porosifying” agent, andthe plug will become more porous after implantation. The effectivedensity of the implant material will change, possibly as soon as thefirst few days, following implantation to be receptive for optimalcellular infiltration. For example, the plug will thus be more conduciveto cellular infiltration and attachment to the remaining fibrouscollagen scaffold, which is important for bone regeneration to occur.

In yet another embodiment, a portion of the implant of the presentinvention can also be formed of a synthetic polymer material (e.g. PTFE,polylactic-co-glycolic acid, etc.). U.S. Pat. No. 5,683,459 (Brekke),assigned to the same entity as the present invention and herebyincorporated by reference, describes methods and apparatus for treatingbone deficiencies with polymer based devices.

The device of the subject invention (e.g. implant, delivery system) maycontain or deliver one or more biologically active or pharmaceuticalagents (i.e., therapies), such as but not limited to those disclosed inTable 2.

TABLE 2 Examples of Biological, Pharmaceutical, and other ActiveIngredients Deliverable via the Present Invention Adenovirus with orwithout genetic material Angiogenic agents Angiotensin Converting EnzymeInhibitors (ACE inhibitors) Angiotensin II antagonists Anti-angiogenicagents Antiarrhythmics Anti-bacterial agents Antibiotics   Erythromycin  Penicillin Anti-coagulants   Heparin Anti-growth factorsAnti-inflammatory agents   Dexamethasone   Aspirin   HydrocortisoneAntioxidants Anti-platelet agents   Forskolin Anti-proliferation agentsAnti-rejection agents   Rapamycin Anti-restenosis agents AntisenseAnti-thrombogenic agents   Argatroban   Hirudin   GP IIb/IIIa inhibitorsAnti-virus drugs Arteriogenesis agents   acidic fibroblast growth factor(aFGF)   angiogenin   angiotropin   basic fibroblast growth factor(bFGF)   Bone morphogenic proteins (BMP)   epidermal growth factor (EGF)  fibrin   granulocyte-macrophage colony stimulating factor (GM-CSF)  hepatocyte growth factor (HGF)   HIF-1   insulin growth factor-1(IGF-1)   interleukin-8 (IL-8)   MAC-1   nicotinamide   platelet-derivedendothelial cell growth factor (PD-ECGF)   platelet-derived growthfactor (PDGF)   transforming growth factors alpha & beta (TGF-.alpha.,TGF-beta.)   tumor necrosis factor alpha (TNF-.alpha.)   vascularendothelial growth factor (VEGF)   vascular permeability factor (VPF)Bacteria Beta blocker Blood clotting factor Bone morphogenic proteins(BMP) Calcium channel blockers Carcinogens Cells   Bone marrow cells  Blood cells   Stem Cells   Umbilical cord cells   Fat cells   Bonecells   Cartilage cells Chemotherapeutic agents (e.g. Ceramide, Taxol,Cisplatin) Cholesterol reducers Chondroitin Collagen Inhibitors Colonystimulating factors Coumadin Cytokines prostaglandins Dentin EtretinateGenetic material Glucosamine Glycosaminoglycans GP IIb/IIIa inhibitors  L-703,081 Granulocyte-macrophage colony stimulating factor (GM-CSF)Growth factor antagonists or inhibitors Growth factors   Acidicfibroblast growth factor (aFGF)   Autologous Growth Factors   Basicfibroblast growth factor (bFGF)   Bone morphogenic proteins (BMPs)  Bovine Derived Growth Factors   Cartilage Derived Growth Factors (CDF)  Endothelial Cell Growth Factor (ECGF)   Epidermal growth factor (EGF)  Fibroblast Growth Factors (FGF)   Hepatocyte growth factor (HGF)  Insulin-like Growth Factors (e.g. IGF-I)   Nerve growth factor (NGF)  Platelet Derived endothelial cell growth factor (PD-ECGF)   PlateletDerived Growth Factor (PDGF)   Recombinant NGF (rhNGF)   RecombinantGrowth Factors   Tissue Derived Cytokines   Tissue necrosis factor (TNF)  Transforming growth factors alpha (TGF-alpha)   Transforming growthfactors beta (TGF-beta)   Tumor necrosis factor alpha (TNF-.alpha.)  Vascular Endothelial Growth Factor (VEGF)   Vascular permeabilityfactor (UPF) Growth hormones Heparin sulfate proteoglycan HMC-CoAreductase inhibitors (statins) Hormones Erythropoietin ImmoxidalImmunosuppressant agents inflammatory mediator Insulin InterleukinsInterlukin-8 (IL-8) Interlukins Lipid lowering agents Lipo-proteinsLow-molecular weight heparin Lymphocites Lysine MAC-1 Morphogens Nitricoxide (NO) Nucleotides Peptides PR39 Proteins ProstaglandinsProteoglycans   Perlecan Radioactive materials   Iodine-125   Iodine-131  Iridium-192   Palladium 103 Radio-pharmaceuticals Secondary Messengers  Ceramide Somatomedins Statins Steroids Sulfonyl Thrombin Thrombininhibitor Thrombolytics Ticlid Tyrosine kinase Inhibitors   ST638  AG-17 Vasodilator   Histamine   Forskolin   Nitroglycerin Vitamins   E  C Yeast

Regardless of the time of investment or incorporation of thesetherapies, they may be in solid particulate, solution gel or otherdeliverable form. Utilizing gel carriers may allow for the materials tobe contained after wetting, for some tailorable length of time.Furthermore, additions may be incorporated into the macrostructureduring manufacture, or later. The incorporations may be made by blendingor mixing the additive into the macrostructure or microstructurematerial, by injection into the gel or solid material, or by othermethods known to those skilled in the art. Another method ofincorporating additives, biologics and other therapies, into themacrostructure or microstructure of one or more regions of the device isthrough the use of microspheres.

The term “microsphere” is used herein to indicate a small additive thatis about an order of magnitude smaller (as an approximate maximumrelative size) than the implant. The term does not denote any particularshape; it is recognized that perfect spheres are not easily produced.The present invention contemplates elongated spheres and irregularlyshaped bodies.

Microspheres can be made of a variety of materials such as polymers,silicone and metals. Biodegradable polymers are ideal for use increating microspheres (e.g., see those listed in tables 2 and 3). Therelease of agents from bioresorbable microparticles is dependent upondiffusion through the microsphere polymer, polymer degradation and themicrosphere structure. Although most any biocompatible polymer could beadapted for this invention, the preferred material would exhibit in vivodegradation. Upon review of the present disclosure, those skilled in theart will recognize that there can be different mechanisms involved inimplant degradation like hydrolysis, enzyme mediated degradation, andbulk or surface erosion. These mechanisms can alone or combinedinfluence the host response by determining the amount and character ofthe degradation product that is released from the implant. The mostpredominant mechanism of in vivo degradation of synthetic biomedicalpolymers like polyesters, polyamides and polyurethanes, is generallyconsidered to be hydrolysis, resulting in ester bond scission and chaindisruption. In the extracellular fluids of the living tissue, theaccessibility of water to the hydrolyzable chemical bonds makeshydrophilic polymers (i.e. polymers that take up significant amounts ofwater) susceptible to hydrolytic cleavage or bulk erosion. Severalvariables can influence the mechanism and kinetics of polymerdegradation, e.g., material properties like crystallinity, molecularweight, additives, polymer surface morphology, and environmentalconditions. As such, to the extent that each of these characteristicscan be adjusted or modified, the performance of this invention can bealtered.

In a homogeneous embodiment (i.e., monolithic or composite of uniformheterogeneity) of a therapy delivering implant material, the deviceprovides continuous release of the therapy over all or some of thedegradation period of the device. In an embodiment incorporatingmicrospheres, the therapy is released at a preferential rate independentof the rate of degradation of the matrix resorption or degradation. Incertain applications it may also be necessary to provide a burst releaseor a delayed release of the active agent. The device may also bedesigned to deliver more than one agent at differing intervals anddosages, this time-staged delivery also allows for a dwell ofnon-delivery (i.e., a portion not containing any therapy), therebyallowing alternating delivery of non-compatible therapies. Deliveryrates may be affected by the amount of therapeutic material, relative tothe amount of resorbing structure, or the rate of the resorption of thestructure.

Time-staged delivery may be accomplished via microspheres, in a numberof different ways. The concentration of therapeutic agent may varyradially, that is, there may be areas with less agent, or there may beareas with no agent. Additionally, the agent could be varied radially,such that one therapy is delivered prior to a second therapy—this wouldallow the delivery of noncompatible agents, with the same type ofsphere, during the same implant procedure. The spheres could also varyin composition among the spheres, that is, some portion of the spherepopulation could contain one agent, while the balance may contain one ormore alternate agents. These differing spheres may have differentdelivery rates. Finally, as in the preceding example, there could bedifferent delivery rates, but the agent could be the same, therebyallowing a burst dose followed by a slower maintained dose.

As will be described in greater detail later, the agent may be anysubstance such as a therapeutic agent or enzyme. The agent is preferablya protein such as a degradation enzyme, cytokine or cytokine inhibitorand more preferably a growth factor. As will be appreciated by thoseskilled in the art, combinations of agents may be used and these agentsmay be derived form a variety of sources, synthetic and natural and mayinclude recombinant methods of manufacture. The amount of bioactiveagent in the implant may be adjusted to achieve the desired dosage.Preferable, the implant material contains between about 0.01 ng andabout 300 mg of the active agent per milliliter of implant material. Thedevice could contain more or less depending upon the application forwhich the device is intended and the required activity level of theselected agent. The agent can be contained within the implant in anumber of methods known to those skilled in the art.

The term “therapy” has been used in this specification, in variousinstances; notwithstanding these various uses, many in combination withother agents (e.g., drug, biologic, agent, biologically active agents,etc.), therapy is not meant to be exclusive of these, but rather toincorporate them, and vice-versa. The usage herein is employed to bemore descriptive of potential treatment forms, and not limiting as tothe definition of the term. Additionally, “biologically active agents”may be relatively inert, but may cause a response by their taking upspace, or causing tissue strain or separation.

In yet another embodiment, the implant may incorporate microparticles(e.g. microspheres) dispersed throughout its structure to deliver atherapeutic agent. As is known in the art, microspheres are well knownfor their use in long term controlled release of drugs or otherbeneficial agents. This is a highly developed technology that has beenused in many applications and such microspheres are available from avariety of sources (e.g., Polymicrospheres, Indianapolis, Ind.). Themicrosphere structures typically consists of: (a) a continuous drugphase surrounded by a continuous barrier membrane or shell(microcapsule), (b) a shell structure where the drug phase is subdividedinto numerous domains scattered uniformly through the interior of themicrosphere, (c) a polymer matrix throughout which the drug is uniformlydispersed, (d) a structure where the drug is either dissolved ormolecularly dispersed within the carrier material from which themicrosphere is prepared, or (e) homogeneous solid. The most commonmethod of delivering drugs or other therapeutic agents with microspheresincorporates these agents uniformly within a polymer matrix,additionally this embodiment contemplates radially non-uniform spheresarranged to provide time-staged delivery of therapies.

The subject invention can also incorporate cellular additions. Cellularmaterial may be delivered in combination with or independent of drugdelivery. The cellular material may be present on the inside of theimplant, outside of the implant, or incorporated within the implant in aporous construct, laminate or other such embodiment. The cellularmaterial may be added to the implant immediately prior to insertion intothe body of the living being or may be grown on the implant in the daysor weeks prior to implantation so more mature cells are in place whenthe device is implanted. If the cells are seeded on the implant severaldays or weeks prior to implantation, the implant may be placed in anin-vitro setup that simulates the in-vivo environment (e.g., where bloodor a blood substitute medium is circulated at appropriate pressure andtemperature) to acclimate the cells to the intravascular environment.The cell-seeded implant may be incubated in this in-vitro setup atphysiologic conditions for several days prior to implantation within thebody. Cell seeding techniques have been developed for a variety of celltypes. Examples of cellular material that may be seeded on implant arelisted in the following Table 3.

TABLE 3 Cellular Material Deliverable Via this Invention Adipose cellsBlood cells Bone marrow Cells with altered receptors or binding sitesEndothelial Cells Epithelial cells Fibroblasts Genetically altered cellsGlycoproteins Growth factors Lipids Liposomes Macrophages Mesenchymalstem cells Progenitor cells Reticulocytes Skeletal muscle cells Smoothmuscle cells Stem cells Vesicles

It is also conceived that a source of cytokines or growth factors (e.g.platelet-rich plasma, bone marrow cells, etc.), whether synthetic,autologous or allograft in origination, can be delivered with the deviceof this invention (e.g. incorporated into the implant or delivered viathe delivery system). For example, it is known that one of the firstgrowth factors to initiate the cascade leading to bone regeneration areplatelet-derived growth factor (PDGF) and transforming growthfactor-beta (TGF-β). Each of these growth factors is derived from thedegranulation of platelets at the wound, defect or trauma site. It isbelieved that increasing the presence of such platelets at the wound ortrauma site can increase the rate of healing and proliferation needed toregenerate bone.

The application of platelet-rich plasma (PRP) or other autologous bloodcomponents is one way to deliver a highly concentrated dose ofautologous platelets. PRP is easily prepared by extracting a smallamount of the patient's blood and processing it, for example usinggradient density centrifugation, to sequester and concentrate thepatient's platelet derived growth factors. Other preparation methodsremove water from the buffy coat and utilize filtering systems toconcentrate platelets and fibrinogen. It is believed that applying PRPor other autologous growth factors to the wound site in conjunction withthe subject invention will increase the amount of PDGF and TGF-βavailable for jump-starting the healing process. PRP can be prepared forprocedures with small volumes of blood, drawn by the doctor or nursepre-surgically. Typically, 40-100 ml of blood are drawn preoperativelyand placed in a PRP preparation unit. SmartPREP (Harvest TechnologiesCorp., Norwell, Mass.) and UltraConcentrator (Interpore Cross, Irvine,Calif.) are device that have been shown to effectively produce PRP forOR, office implant, and periodontal uses.

Once the PRP is prepared, other additives (e.g. activator, growthfactor, drug, chemical, bone, etc.) can be added to the plasma. Forexample, an activator can be used to gel the PRP material prior toapplication to the implant device or delivery to the surgical site. Onesuch activator includes 5 ml of 10% calcium chloride with 5,000 units oftopical bovine thrombin (GenTrac, Middleton, Wis.). Depending upon theflowability of the PRP, the type and quantity of activator can beadjusted. For example, to infuse the implant material of this inventionwith a PRP gel preparation, the ratio of ingredients would include ahigher proportion of PRP to allow the PRP to more effectively flowthrough and permeate through the porous implant material. It is alsoconceived that the implant material (e.g. cylinder or other biomaterialimplant) can be inserted into the PRP preparation unit (e.g. centrifuge,concentration unit). In this fashion, the platelets can be concentratedright into or onto at least a portion of the implant directly. Forexample, some PRP devices include a centrifuge for separation of theblood components. The biomaterial implant could be positioned within thecentrifuge such that the desired blood constituent is directed into theimplant material during processing.

The advantages of an autologous growth factor application such as PRPwould be twofold. First, the significant fibrin and fibronectincomponents of the PRP enhances cell adhesion and induces osteoconductionby providing a structure onto which precursor cells can migrate and bonecan grow. Second, it amplifies the influence of PDGF and TGF-B, whichare formed as the platelets degranulate. The addition of exogenouslydelivered amounts of highly concentrated PDGP and TGF-B promotes anamplified cascade that results in increased cellular population andsubsequent expression of more growth factors. This benefit can play arole in the healing process and can lead to more rapid and effectivetissue regeneration. This may be attributed to the concentrated levelsof fibrin, PDGF, TGF-B, as well as other growth factors or proteins thathave not as yet been identified.

Other autologous materials can also be incorporated into and or used inconjunction with the subject invention (e.g., autologous bone marrowcells (BMC)). Bone marrow contains osteogenic progenitor cells that havethe ability to form and repair bone. The marrow can be harvested anddispersed into single cell suspensions. The cells can then beconcentrated (e.g. through filtering, centrifucation) or used as is. Theresulting mixture can be diluted and implanted into the wound site,incorporated into the implant material, or delivered by the deliverysystem of the subject invention.

The use of growth factors such as PRP or progenitor cells from BMC areparticularly beneficial for patients with risk factors that typicallyreduce the success of bone grafts and osteointegration, including theedentulous, severely atrophic maxilla, and patients with osteoporosis.Combining growth factors and progenitor cells with absorbable deliverysystems could result in significant changes in the outcomes we canexpect for guided tissue regeneration.

There are many other materials which can be used to construct theimplant or a portion thereof. Table 4 below lists some of the possiblematerials which can be used either as fillers or as the main construct.This list is not complete but is only presented to as a non-limitingexample of some of the materials which may be used for this invention.

TABLE 4 Examples of Materials Suitable for Filler or for the MainConstruct of the Present Invention Alginate Calcium Calcium PhosphateCalcium Sulfate Ceramics Chitosan Cyanoacrylate Collagen DacronDemineralized bone Elastin Fibrin Gelatin Glass Gold Hyaluronic acidHydrogels Hydroxy apatite Hydroxyethyl methacrylate Hyaluronic AcidLiposomes Mesenchymal cells Nitinol Osteoblasts Oxidized regeneratedcellulose Phosphate glasses Polyethylene glycol PolyesterPolysaccharides Polyvinyl alcohol Platelets, blood cells RadiopacifiersSalts Silicone Silk Steel (e.g. Stainless Steel) Synthetic polymersThrombin Titanium

In addition to pure polymer materials, additives may be combined withthe polymers to improve their mechanical, biological, or resorptioncharacteristics. One example of additives would be plasticizers whichcan alter the mechanical performance of polymers to make them moreelastic or deform more plastically. Another additive may benanoparticles which increase the strength and may change the resorptionproperties of polymers. Additives can be incorporated into the polymerswith standard melt compounding, solvent mixing, or other processes knownin the art. Examples of plasticizers and nanoparticles are shown in, butnot limited to, Tables 5 and 6.

TABLE 5 Polymer Plasticizers which may be Useful in the PresentInvention 1,2-cyclohexadione Acetoxytriethyl citrate Acetylated coconutoil (EPZ) Acetyltri-n-butyl citrate Acetyltri-n-hexyl citrateActyltriethyl citrate Adipate esters Benzoic acid-2-hydroxyacetateBis-2-methoxyethyl phthalate Calcium stearate Camphor CaprolactoneCitrate esters Dibutylphthalate Diethyl phthalate Dioctyl adipateEpoxidized soy oil Ethyl benzoate Ethyl-, butyl-, and hexyl-esters ofacetylated citric acid Ethyl-terminated oligomers of lactic acidGlycerol Glyceryl triacetate Glycolide Hexamethylbenzene Lactide Linseedoil Lipids Liposomes n-Butyryltri-n-hexyl citrate Oil Pthallic estersPolyurethane Stearic acid Tributyl citrate Triethyl citrate

TABLE 6 Nanoparticles Silica Clay Metals Aluminum Oxides CeramicsPolymers Metal Oxides

When implanting a material into the tissue of a living being (e.g. forthe purpose of treating a wound or defect) it is generally importantthat the implant is physically and chemically compatible with the hosttissue. “Integrity matching,” as used herein, refers to processing thatalters the strength of the implant, such that the resulting strengthmatches or nearly approximates the strength of the organic host tissue.Porosity matching refers to processing that alters the pore structure(i.e., size, shape, and/or population), in the implant, such that theresulting porosity matches or nearly approximates the pore structure ofthe organic host tissue. Compliance matching refers to compressiveprocessing that tailors the implant compliance (e.g., modulus and/orcoefficient of restitution, etc.) such that it matches or nearlyapproximates the compliance of the organic host tissue. Structurematching refers to any process utilized to create a structure similar tothe host tissue (e.g., fibrous nature or other heterogeneities). Weightmatching refers to processing that alters the molecular weight of theimplant's matrix, such that the resulting molecular weight matches ornearly approximates the molecular weight/structure of the organic hosttissue. Separately, together, or in any combination, these “matching”processes are referred to as bio-matching; said bio-matching processesbeing utilized to create a “bio-matched” implant.

A portion of the implant of one bio-matched embodiment of this inventioncan be formed of a ceramic material such as calcium phosphate, calciumcarbonate and calcium sulfate or other derivates. Examples of productsconstructed of these materials include Wright Medical Technology'sOsteoset™ (Arlington, Tenn.), BioGeneration's ProFusion™ (Arlington,Tenn.), Encore's Stimulan™ (Austin, Tex.), Norian Corporation's SRS™(Cupertino, Calif.), and Interpore Cross' ProOsteon™ (Irvine, Calif.).

There are numerous ceramic systems that display both biocompatabilityand degradability. In the body, the bone itself is the naturalstorehouse of minerals. The major mineral component of bone ishydroxyapatite, a form of calcium phosphate. Other calcium phosphatesalts in bone include monotite, brushite, calcium pyrophosphate,tricalcium phosphate, octocalcium phosphate, and amorphous calciumphosphate. Additionally, bone contains calcium carbonates.Hydroxyapatite and tricalcium phosphate are the most widely studied ofthe calcium phosphates, which have calcium to phosphate ratios ofbetween 1.5 to 1.67 respectively. Calcium phosphate, Ca₁₀(PO₄)₆(OH)₂, isknown as a physiologically acceptable biomaterial which is useful as ahard tissue prosthetic. Another calcium mineral used as a bonereplacement material is calcium sulfate. Most of the calcium-basedbiomaterials can be molded under high pressure, thereby effectingintegrity and strength. Pores may be useful to assist host matrices inosteoconduction, and pores may be formed in molded calcium phosphate bycompaction of calcium phosphate powders containing naphthalene followedby removal of the naphthalene by leaching or sublimation. Hydrothermalexchange of marine coral structures (i.e., calcium carbonate for calciumphosphate), and decomposition of hydrogen peroxide are other methods togenerate a pore-filled structure. The dense forms of the calciumphosphate implant have mechanical properties equal to or exceeding thatof natural bone, but their porous forms typically do not. Certainprocessing steps, such as these, and others known to those skilled inthe art, may be used to tailor the physical and mechanical properties ofthe resulting implant.

In addition to drugs and biologics, coatings may be added to the implantto enhance the performance of the device. The coating may increaselubricity for improved insertion, increase thrombogenicity to promotehemostasis and platelet deposition, or provide other advantages to theimplant. The coating may also be used as a mechanical barrier to protectunderlying cellular material which may be incorporated onto the implantmaterial to work in concert with the agent delivery aspects of theinvention. Examples of possible coating materials are listed in Table 7.

Additionally, an embodiment of the current invention may comprise acalcium salt and a native-collagen matrix. This may be accomplished byfirst forming a specialized collagen suspension of native insolublecollagen fibers suspended in a soluble collagen slurry of desirableviscosity, in which the ratio of soluble to insoluble fibrous collagenis maintained in the range of about 1:20 to 10:1. Into this slurry isadded a calcium salt such as calcium sulfate. Enough calcium salt shouldbe added to the slurry to ensure that the final product will have thedesired weight percentage of calcium salt, between about 10% and 90%.The final product can be made in a number of methods. In one suchmethod, the solution is fully homogenized and poured into molds or largesheets of the desired shape or thickness, and it is recognized thatthere exists other techniques known in the art that should provesufficient for these applications. The product is then lyophilized inthe manner described previously. The material thus produced may also betreated with optional crosslinking treatments (e.g. chemical,dehydrothermal, gamma radiation, ethylene oxide, or ultravioletradiation) as will be understood by those skilled in the art upon reviewof the present disclosure.

TABLE 7 Example Materials for Use in Coating the Present InventionAlbumin Alkyl methlacrylates Glycosaminoglycans Heparin Hyaluronic acidHydrophilic polymer Integrins Paralyne Phosphorylcholine PhospholipidsPolyacrylamide Polyanhydrides Polyethylene acetate Polyethylene glycolPolyethylene oxide Polypeptides Polyurethane Polyvinyl alcohol Polyvinylpyrrolidone Silanes Silicone

The implants of the present invention are placed within the tissue toenhance or stimulate healing. Also, by combining the use of theseimplants with other surgical devices such as sutures, screws, pins androds, the effectiveness of tissue repair can be greatly enhanced (e.g.serve as a site for attachment of a second tissue).

The subject invention can be utilized to repair or treat wounds in avariety of tissues. Tissue is typically described as an aggregation ofsimilarly specialized cell united in the performance of a particularfunction. The implant structure and material can be manipulated(integrity matched) so as to closely approximate the mechanicalproperties (e.g., stiffness, compressibility) matching the surroundingtissue. Implant materials can be designed to match the mechanicalproperties of bone, cartilage, tendon, skin, ligament, arteries, etc. Asa non-limiting example, the device can be utilized to treat or healdefects in bone. Bone is a unique connective tissue with a hardextracellular collagen matrix that is impregnated with a mineral,principally hydroxyapatite. In general, there are two forms of bonetissue: cortical and cancellous as will be described later.

There are many other tissues that can be repaired using the implant or aportion thereof. Table 8 below lists some of the possible tissues andprocedures that can use this invention. This list is not complete but isonly presented to as an example of some of the tissues or procedureswhich may be used for this invention.

TABLE 8 Examples of Tissues and Procedures Potentially Benefiting fromthe Present Invention Bone Bone tissue harvest Spinal arthrodesis Spinalfixation/fusion Osteotomy Bone biopsy Maxillofacial reconstruction Longbone fixation Compression fractures Hip reconstruction/replacement Kneereconstruction/replacement Hand reconstruction Foot reconstruction Anklereconstruction Wrist reconstruction Elbow reconstruction Shoulderreconstruction Cartilage Mosaicplasty Meniscus Dental Ridge augmentationThird molar extraction Tendon Ligament Skin Topical wound Burn treatmentBiopsy Muscle Dura Lung Liver Pancreas Gall bladder Kidney Nerves ArteryBypass Surgery Cardiac catheterization Heart Heart valve replacement

In a time-phased delivery embodiment, the implant may be constructed toeffect a tailored delivery of active ingredients. Both the presence ofthe implant and delivery of the select agents is designed to lead toimprovements in patients with tissue defects, as a result of deliveringin no certain order: (1) a substratum onto which cells can proliferate,(2) a drug or biologic which can act as a signaling molecule which canactivate a proliferating or differentiating pathway, (3) a drug orbiologic which may act as a depot for nutrients for proliferating andgrowing cells, and (4) a drug or biologic which will prevent an adversetissue response to the implant, or provide a therapy which reducesinfection and/or treats an underlying disease or condition.

Referring now to the drawings, FIG. 1 illustrates one of the preferredembodiments of a tissue defect treatment system 10 of the presentinvention. As shown in FIG. 1, tissue defect treatment system 10generally comprises a sheath 12, a mass of implant material 14 and anapplicator 16. The treatment system is suitable for open, laparoscopic,arthroscopic, endoscopic and other surgical procedures known fortreating a variety of injuries or maladies.

Sheath 12 generally comprises a tubular housing 18 defining a lumen 19,a hub 20 disposed at the proximal end of housing 18, and an outlet 13 atthe distal end. The hub 20 is provided, at its proximal end, with aflange 21, which is designed to serve as a finger grip. The treatmentsystem 10 can be rigid or flexible depending upon the application. Thesheath 12 or applicator 16 may be lubricated to reduce friction orotherwise ease the placement of the implant material. It may also bedesirable to provide a tubular housing 18 fabricated from a transparentmaterial such as Lexan™ for purpose of visualizing the delivery ofimplant material 14 through the tubular housing 18. In general, thetubular housing 18 is an elongated member preferably constructed of asufficiently small outside diameter, e.g., 5 mm to 10 mm, and somewhatflexible pliable biocompatible material suitable for use in surgicalprocedures (e.g., a gamma-sterilizable material), and is preferablycomposed of a durable plastic material such as Teflon, polyethylene orpolyurethane or possibly a metal.

When required for an arthroscopic procedure, the outer diameter andcross-sectional configuration of housing 18 are chosen so as to permitsliding passage, with minimal clearance, through the channel of alaparoscopic cannula (e.g. trocar) or incision. In a preferredembodiment, the sheath is circular in cross-section, with the outerdiameter being in the range of between about 3 to about 10 mm. Thesedimensions are generally suitable for existing laparoscopic orendoscopic cannula. The actual sizing, however, will vary depending onthe procedure and circumstance, as will be readily appreciated by thoseskilled in the art.

Applicator 16 basically comprises an elongated, cylindrical rod-likeplunger 22 having a thumb plate 24 disposed at its proximal end andhaving a distal end 15. Plunger 16 will generally be fabricated of apliable biocompatible material suitable for use in surgical procedures(e.g., a gamma-sterilizable material), and is preferably composed of aplastic material, such as polypropylene, polycarbonate, or polyethylene.The sizing of the outer diameter of plunger 22 is selected so that ithas a cross-section and configuration that permits sliding passage withminimal clearance through lumen 19 of tubular housing 18 to push orforce the implant 14 through the outlet 13.

In order to effectuate the movement of the pusher from the retracted tothe extended position, the tubular housing 18 includes a collar having aflanged projection 21 arranged to be grasped by the fingers of the userof the device 10. In addition, the proximal end of the applicator 16includes an enlarged cap 24 arranged to be engaged by the user's thumb.Thus, to effect the ejection of the implant 14, the user of the device10 merely has to grasp the projection 21 with his/her fingers whileapplying pressure to the cap 24 with his/her thumb. This action forcesthe pusher down the tubular body to the extended position therebyejecting the implant 14. Thus, the applicator 16 is arranged to be movedfrom a retracted position, like that shown in FIG. 1, to an extendedposition, like that shown in FIG. 8, wherein its distal end 15 islocated close to the outlet 13 of the tubular housing 18 (e.g. thelength of plunger 22 is selected so that when thumb plate 24 abutsfinger grip 21 of hub 20, the distal end of plunger 22 will align withthe distal end of sheath 12). In a preferred embodiment, plunger 22 iscomposed of a solid plastic material with a blunt distal end forengaging and advancing implant material 14 through and out of sheath 12.

Preferably, the implant 14 is preloaded in the delivery system prior tothe latter's insertion into the patient's body. The implant 14, forsolid or rigid implant materials (e.g., not readily flowable) is sizedso that the fit between the implant and the inside of tubular housing 18is such that the implant will not inadvertently drop out of the sheathunless advanced by the plunger 22. If necessary, a looser or tighter fitcan be provided by adjusting the size of the implant or the internaldiameter of the sheath 12.

Alternatively, a number of methods could be used to retain the implantwithin the sheath 12 until the device is properly positioned. Forexample, the distal tip 13 of sheath 12 can be constructed to bedeformable to provide valve-like properties (e.g. duckbill valve) thatwould hold the implant within the delivery system until the implant isadvanced by the plunger 22. The deformable tip could be fabricated fromelastomers such as polyisobutane (i.e. rubber) or plastics such aspolyethylene. A removable cap, a dimpled distal tip, or other retentionmeans could also be used, as well as other methods known to thoseskilled in the art.

As shown in FIG. 2A, the embodiment of the implant 14 is formed of densepolymer (e.g. collagen) foam with long native collagen fiberreinforcement. The implant is compressed prior to loading into thedelivery system so that it has a high expansion ratio (wet-to-dry) andgood mechanical wet strength. The implant may contain particles of acalcium derivative such as, but not limited to, calcium sulfate orhydroxyapatite throughout the implant to enhance the healing properties.The open pores of the implant allow body fluids and cells to permeatethe implant during the healing process, or to facilitate the healingprocess. This and other embodiments of the device can be constructedfrom various polymers as described previously. In general, the grossstructure of the devices is composed of biologically acceptable,biodegradable polymer arranged as a one or more piece porous body withinterconnecting voids. In some cases it may be desirable that each voidcommunicates with a large proportion of the other voids. Depending uponthe application, the voids or pores may be uniformly or randomly sized,positioned and shaped. For example, an implant with an interconnecting,open-cell meshwork, would duplicate the architecture of human cancellousbone from the illiac crest and when fabricated form suitable materials(e.g. polymers) possess physical property (strength) values in excess ofthose demonstrated by human (mammalian) illiac crest cancellous bone.

FIG. 2B depicts implant 14 after it has expanded in diameter, implant14E, after being released from the sheath and in response to the bodyfluids. In the preferred embodiment the implant 14 is a slightlyexpandable member which can be contracted or compressed compact to fitwithin the interior of the tubular housing 18, but it changes (e.g.,expands) to a configuration suitable for filling and treating the woundor defect in the tissue (e.g., when either unconstrained by the tubularhousing, in contact with body fluids, at body temperature, etc.).

As will be described later, the implant can be compressed to any degreeto provide for a good fit within the delivery system and the tissuewound. Compression will also increase the effective density and mass ofthe implant and may be useful for controlling resorption time or postprocedure strength (integrity matched). In some cases it may bepreferable to provide an implant which is not compressed. In the eventthat a solid implant is not compressed, a retention cap or retentionband can be used to hold the implant 14 within the tubular housing 18until time for delivery.

As previously described, the implant material 14 may be composed of awide variety of biocompatible materials, preferably a bioresorbablematerial (e.g., polymer, collagen), and preferably incorporating nativefibrous collagen. The implant material may be in any form, which issuitable for delivery through the treatment system. For example, it maybe in the form of a loose fibrous material, (e.g., a cottony orfleece-like material), a sponge, a paste or flowable form, a foldedmembrane, a woven or non-woven sheet, compressed/fused granules orpellets. As mentioned earlier the implant is preferably formed of abioresorbable (e.g., biodegradable) material. This feature enables theimplant to be left in place until the bodily tissues resorb itthereafter. Accordingly, the implant does not have to be removed afterhaving served its purpose.

While the implant 14 may be composed of any biocompatible material,native fibrous collagen is believed very suitable for at least one ofthe implant constituents. The physical form of implant 14 may varywidely, with the one selected by the physician being dependent on thecircumstances of the case. In alternative embodiments, implant 14 maycomprise a combination of one or more types of materials (e.g.,collagen, synthetic polymer, and ceramic). The implant 14 may comprise asponge-like portion and a loose fibrous portion, wherein the loosefibrous portion is disposed at the most distal end of sheath 12.Alternatively, the implant 14 could comprise a flexible portionsurrounding a more rigid structural portion. It will be appreciated thatthis arrangement would first provide a flexible material (e.g. collagen,polymer foam) for intimate contact with the wound site, that isreinforced with a more solid material (e.g. synthetic polymer pin)backing (sponge) for applying pressure over the entire surface of ableeding site said pressure being the same hydrostatic pressure normallyseen at the site (e.g., compliance matched) or somewhat higher. Multiplecomponent implant devices may be joined together or may be structurallyseparate and independent. Other combinations and their advantages willreadily be apparent to those skilled in the art.

In a preferred embodiment, at least a portion of the implant is porous.The pore size can vary depending upon the process by which implant 14 isprocessed. Preferably, porosity may be more than 50% of the respectivestructure/material volumetric area. Moreover, pore size can rangebetween 25 and 1000 um. However, it is to be appreciated that poredensity as well as pore size can vary outside these ranges dependingupon the particular manufacturing process chosen. It may also bedesirable to have portions of the implant that are non-porous.Preferably, implant 14 is manufactured having a porosity which generallymatches the architecture of the surrounding tissue (e.g., porositymatched or structure matched), into which implant 14 is placed. Thus,depending upon the specific application desired, the method ofmanufacturing and or the material of implant 14 can be adjusted tocontain pores of varying size and population. It is conceivable that theporosity of the implant may change over time. For example, the implantmay be fabricated from a porous resorbable polymer macrostructure (U.S.Pat. No. 4,186,448, Brekke) where the pores of the macrostructure arefilled with a microstructure material that degrades more rapidly thanthe porous macrostructure. After implantation, the microstructure maydegrade or resorb leaving larger effective porosity. Moreover, implant14 can be manufactured having architecture and mechanical properties(such as stiffness and compressibility; structure matched, integritymatched or compliance matched, respectively) to substantially match thearchitecture and/or mechanical properties of surrounding tissue intowhich implant 14 is placed.

Tissue implant 14, can contain materials of possibly different porosityand/or mechanical properties. As such, the implant can be particularlyadapted for placement into a juncture region adjoining tissue areashaving dissimilar porosity and/or mechanical properties. The structureand materials of implant 14 correspondingly can be modified to haveporosity and mechanical properties such as stiffness, compressibility,etc. to substantially match the properties of the tissue juncture regionafter implantation (bio-matching), as is discussed and describedelsewhere herein.

It should be noted at this juncture that the implant can be of anysuitable shape and need not be of the cylindrical-like shaped implant 14shown in FIG. 2A, so long as it can be effectively placed into positionat the situs of the wound. FIG. 2C depicts an alternative embodiment ofthe implant 40 with a generally cylindrical body 44 and an oversizedcylindrical head 42. The cylindrical head can be made of the samematerial as the body 44 of the implant or of an alternative material.For example, head 44 can be comprised of a more rapidly resorbingmaterial such as soluble collagen. The head could be used to promotehemostasis at the wound site and then rapidly resorb leaving the longerterm resorbing cylindrical body 44 in the wound to provide a structuralmatrix for tissue regeneration. The head 42, or body 40, of implant 40could also contain select biologics or agents such as thrombin to assistin achieving hemostasis. The head 42 of device 40 could also be used tolimit the depth to which the device is implanted. The head 42 could beutilized as an impact surface for hammering the implant into the tissuedefect, much like the head of a nail. In this application the head wouldbe fabricated of an appropriately resilient material and could beremovable after the device 14 is implanted.

FIG. 2D depicts yet another embodiment of the implant, implant 46 thatis constructed in a generally conical fashion. Implant 46 has a taperedtip 47, and a widened base 48. The tapered nature of the implant mayallow a better compression fit into the defect site. This implant may besuitable for non-cylindrical (e.g., tapered) defect sites.

Referring now to FIG. 2E, an alternative embodiment to the implantdevice 14 is shown and designated by the reference number 54. As can beseen, the implant 54 basically comprises a generally elongated structurethat is preferably formed of a sheet or film 53 which is reeled up abouta mandrel (not shown) to form a tube. The structure could be formed of alamination of similar sheets to create the final implant device. Thetubular member 54 could also be formed of a variety of differentmaterials described herein (e.g., ECM, collagen, polymer,polysaccharide, etc.) in a variety of configurations (e.g., powders,fibers, pellets, spheres, etc.) that can be rolled up or laminatedtogether. For example, by utilizing multiple sheets of differentmaterials the implant could be designed to have varying degradationrates (e.g. multi-stage), varying porosity for tissue in-growth, andstaged release of agents or biologics (e.g., thrombogenic drugs, growthfactors). It is also conceived that the implant 54 having a centralpassageway 55 extending longitudinally therethrough for accommodating aguide pin or other guiding element (not shown) that can be used todirect the implant to the desired implant site. The guide element couldbe removed or left in place. The pin could also extend beyond the distalportion of the implant and serve to stabilize or anchor the implantwithin the defect site.

Referring now to FIG. 2F, a further alternative embodiment to theimplant device 14 is shown and designated by the reference number 56. Ascan be seen, the implant 56 basically comprises a generally elongatedcylindrical structure that is preferably formed of an outer sleevematerial 57 and an inner core material 58. Essentially the implant isformed of a rod or bar of material with a longitudinal passageway formedtherein in which another material is placed that extends through atleast a portion of the rod or bar. Sleeve 57 could be constructed of ahemostatic material to minimize bleeding after placement. Sleeve 57could also be constructed to resorb more quickly as the surroundingtissue regenerates through its periphery. The inner core 58 could thenresorb more slowly to provide a longer term structural substrate fortissue regeneration. It is also conceived that implant 59 could containan open central passageway extending longitudinally therethrough foraccommodating a guide pin or other guiding element (not shown) that canbe used to direct the implant to the desired implant site.

Referring now to FIG. 2G alternate implant 50, comprising essentially acompound or composite structure formed of a first structure/material 51and a second structure/material 52. Although the compound structureembodiment of FIG. 2G is shown with two different constituents, theimplant could be fabrication from any number of different elementscombined together to achieve a desired result. With respect the FIG. 2G,the first structure/material 51 and second structure/material 52 arepreferably made from biocompatible materials. The firststructure/material 51 is connected to second structure/material 52,wherein structure/material 14 includes a body having dissimilarmaterials, therapies (e.g., drugs, biologics) or properties (e.g.,mechanical, porosity, wetability) properties from material 12. Bothmaterials 51 and 52 may include therapeutic agents within the pores ofthe materials or mixed within the structure of the material. Implant 50can be particularly useful for placement into any physiological systemhaving a juncture between dissimilar types of tissue. Any region joiningtwo dissimilar types of tissue (i.e., bone, cartilage, tendon, skin,ligament, cementum, etc.) can be implanted with the bonded dissimilarstructure/materials 51 and 52 of implant 50. By connecting eachstructure/material together and implanting the combination within atissue juncture, carrier/implant 10 ensures the tissue juncture remainstogether during the repair process, which may help to promote rapidhealing. It is also conceivable that one portion of a tissue defect maybe somewhat more vascularized and prone to bleeding, as such, thecompound structure embodiment of FIG. 2G could be designed to have oneportion which is comprised of a hemostatic material (e.g. collagen) tohelp stop bleeding. The materials can be manufactured adjacent to oneanother during processing (e.g. lyophilization) or can be bonded (e.g.,thermal weld, solvent weld, mechanically connected, etc) at a latertime.

Referring now to FIG. 2H, which depicts alternate implant 59 comprisingessentially a cylindrical structure that has one or more ridges or barbs60 which can serve to anchor the implant into the tissue and act toprevent the device from being pulled out or dislodged after placement.The ridges or barbs 60 are formed on the outer surface of implant 59.The barb is preferably a circular ridge extending about thecircumference of the body. The sharpness or angularity of the barb 60may be adjusted depending upon the application and the material of theimplant. The trailing edge of the barbs grips the sides of a borehole ina bone or other tissue. A blunt tapered tip is formed on the distal endof the body of implant 59. A trailing end of the body of implant 59 islocated at the opposite end of the body from the distal end. Thisembodiment as well as others could also be sutured, stapled, glued orotherwise fixed in position after implantation.

The embodiment of implant 61 shown in FIG. 3 is a “flowable” implantcomprised of a flowable material, such as but not limited to, collagenpaste, cyanoacrylate (glue/adhesive), thrombin glue, hydrogel, growthfactor gelatin, etc. The flowable material can be stored in a tube (notshown) and dispensed into the tissue defect by a needle-like device,such as a syringe (not shown). The flowable material can be designed toharden slightly after placement, like an epoxy or silicon caulkingmaterial, so that it is not extruded from the puncture during tissuemovement or flexing. The material could also photopolymerize likeFocalSeal (Focal, Inc., Lexington, Mass.). The implant could containdrugs or other agents as described previously. The flowable materialcould be designed to have porosity by incorporating citric acid, or someother “foaming” agent, that would create pores in the implant duringand/or after placement; mixing the foaming agent immediately prior toimplant injection would allow foaming to occur primarily followingimplant, chilling the implant material would also slow the foamingreaction until the implant warmed to body temperature. The implant couldalso be formed by flowing two or more materials together (e.g. two-partepoxy) into the defect site such that the combination of materialssuitably fills the defect site and serves to treat the wound.

The implant 14 of this invention is suitable for introduction into awound, defect or incision in a variety of body tissues or organs (e.g.,bone, muscle, artery, dura, lung, liver, gall bladder, etc.). Forillustrative purposes, we will describe the use of this device fortreating a defect in bone, particularly a defect in long bones. Longbones (bones of the arms and legs) and the vertebrae share many commonanatomic and biological structures. FIG. 4 depicts the human femur 63,tibia 62, and fibula 64.

FIG. 5 depicts a sectional view of femur 63. All long bones (e.g.,femur) are composed of a shell of dense, strong tissue encasing a lessdense or hollow interior. This construct maximizes strength andminimizes the overall weight, allowing the bones to provide structuralsupport and mobility without encumbering the mobility of the organism.It is important to note that bone is living tissue that contains livingcells that must receive oxygen and nutrients from the blood system tosurvive. At the macroscopic level there are two major forms of bonetissue: compact or cortical; and cancellous or trabecular. The locationof these bone types in a femur is illustrated in FIG. 5, and discussedlater. Cortical or compact bone is a dense material with a specificgravity of about 2. Cancellous bone tissue, also termed trabecular bone,is a sponge-like, open-celled network of calcified collagen fibers. Thefibers of the cancellous bone act like the trusses of a bridge orbuilding construct, providing a lightweight support mechanism for theforces applied to the bone structure.

As shown in FIG. 5, The long bones (bones of the arms, finger, legs andtoes) have a hollow shaft, known as the diaphysis, that is capped oneach end by a solid bone structure, the epiphysis. The diaphysis iscomposed of a cylinder of thick cortical 72, or dense, bone that isencased between an outer layer of periosteum 70, and an inner layer ofendosteal tissue (the endosteum) 74, the internal counterpart to theperiosteum. The periosteal surface is generally very smooth. Like theperiosteum 70, the endosteal tissue layer 74 is constructed from afibrous, leathery structure that provides vascular support for the bonetissue and is rich in osteoblasts, the precursors to osteocytes. It hasa roughened texture, which resembles cancellous bone.

Cancellous bone also exists in the epiphysial and metaphyseal region oflong bones and within the confines of the cortical bone because it iscomposed of short struts of bone material called trabeculae. Theconnected trabeculae give cancellous bone a spongy appearance, and it isoften called spongy bone. There are no blood vessels within thetrabeculae, but there are vessels immediately adjacent to the tissue,and they weave in and out of the large spaces between the individualtrabeculae. Cancellous bone has a vast surface area as would besuggested by its spongy appearance.

The interior of the shaft of a long bone is void of bone tissue.However, this hollow portion, or the medullary canal 76, does containblood cell-producing red marrow in the fetus and young child. As theneed to produce excessive blood cells diminishes, so does the need forthe red blood cell-fabricating marrow. The red marrow is eventuallyreplaced by fatty tissue, often called yellow marrow.

The epiphysis comprises a thin layer of cortical bone or articularcartilage 80 (at the articulating surface of the joint) surrounding thelattice structure of bone fibers composing the cancellous bone 78. Theperiosteum 70 covering the diaphysis extends over the cortical boneregion 77 of the epiphysis 78 and coming into contact with the articularcartilage 80.

Cartilage is, in many ways, very similar to bone tissue. Like bone, itconsists of a network of fibers in which the cartilage cells, orchondrocytes, are embedded. Unlike bone tissue, the fibers are notcalcified, but are embedded with chondroitin sulfate, a gel substance.Also, present in the intercellular space is hyaluronic acid, a viscousmaterial that facilitates the passage of nutrients from the bloodvessels to the cells within the matrix. The collagen or elastin fibersin cartilage are arranged in an irregular manner to serve as a surfacefeature as well as provide compressive strength.

Only approximately 5% of the tissue volume is occupied by chondrocytes,which are not in direct contact with each other. The remaining portionis occupied by the extracellular matrix and the interstitial fluids.There are no vascular, lymphatic, or neural structures in the cartilagetissue causing the chondrocytes to depend on nutrient diffusion ratherthan vascular supply of the material necessary for cell survival. Threetypes of cartilage exist in the human anatomy, hyaline cartilage,fibrocartilage, and elastic cartilage. The most common cartilage inorthopedic applications is hyaline cartilage forming the articularsurfaces of bones and fibrocartilage forming the discs within the jointstructure.

The open cells of the cancellous tissue 78 contain red marrow. Flat andirregular bones such as vertebrae are constructed like the epiphyses oflong bones. An external layer of thin cortical bone, or articulatingcartilage at the portion of the bone forming a joint, encapsulates thecancellous bone tissue. The resulting structure is similar to foaminjection molded parts used in the construction of electronic equipment,where a solid outer shell of plastic supported by an inner core of foamprovides a lightweight construct suitable for resisting the mechanicalstresses applied to the device. As with the cancellous tissue of theepiphysis of long bones, the space within the cancellous bone fibermatrix in flat and irregular bones is occupied by red marrow.

There are a number of injuries or surgical procedures that requiredefects in bone or cartilage to be repaired. In some instances, bone isremoved from one portion of the body, the harvest site, and transferredto another portion of the body to repair a wound or otherwise treat apatient (e.g. cartilage repair, spinal fusion). Depending upon theprocedure being performed, the implant of the subject invention may besuitable for the original tissue defect and also beneficial for treatingthe harvest site. One such surgical procedure that creates a harvestsite is the Arthrex (Naples, Fla.) Osteochondral Autograft TransferSystem (OATS) for treating full thickness femoral condylar defeats inthe knee. This procedure uses a series of thin-walled cutting tubes toharvest autogeneous plugs of bone capped with healthy hyaline cartilagewhich will be transferred to the damaged area. These osteochondral coreautografts are then press fit into one or more sockets created in thecondylar defect.

The OATS technique may be carried out arthroscopically or as an openprocedure based on surgeon preference and the location and extent of thechrondral defect and harvest site. The preferred donor site is lateralon the lateral femoral chondyle just above the sulcus terminalis. Thisarea has a convex curvature on its articular surface similar to that ofthe central weight-bearing areas of both femoral chondyles.

Donor sockets are routinely left open after these types of tissueharvesting procedures.

FIG. 6 depicts a close-up illustration of the femur tibia joint 82 shownin FIG. 4. Tissue defects 84, 85, and 86 are shown. Defects 84 and 85extend through the articular cartilage layer 80 and into the cancellousbone. Tissue defect 86 is shown extending into the cancellous bone (see78 of the femur 63, in FIG. 5).

The application of the implant of the subject invention to the tissuedefect will now be described. According to the procedure of the presentinvention and as shown in FIG. 7, the surgeon positions the distal endof sheath 13 at the defect site 32 of the tissue 30. As shown in FIG. 7the sheath tip 13 can be sized to abut the outside of the wound site orthe sheath tip could be sized to fit within a portion of the wound (notshown). Once the treatment system 10 is properly positioned, the surgeonapplies pressure to thumb plate 24 of applicator 16. As plunger 22slides through sheath 12 it advances the implant material 14 until thematerial exits the sheath. Note, the length “L” of the proximal end ofthe plunger extending from the proximal end of sheath 12 may becalibrated to exact length of the implant device 14, so that the surgeoncan accurately determine when device 14 is just fully within the distalend of sheath 12. The indicator markings 11 allow the surgeon to gaugehow far the implant is advanced into the tissue defect. As shown in FIG.8, when thumb plate 24 of applicator 16 abuts hub 20, the physicianknows that implant 14 has been pushed entirely out of lumen 19 and thatthe distal end of plunger 22 is substantially flush with the distal endof sheath 12. The surgeon can alternatively directly visualize theplacement of the implant when a transparent or translucent material isused for sheath 12. As the advancing implant 14 engages the tissuedefect site, the physician will encounter resistance at thumb plate 24.He/she then may maintain axial pressure so as to hold the implant 14against the defect site. In the instance where the defect site isbleeding, the implant 14 may be mechanically held against the site ofbleeding to achieve immediate hemostasis. As the implant material (e.g.collagen) begins to interact with bleeding tissue, self-sustaininghemostasis begins to take over, and shortly thereafter mechanicalpressure will no longer be needed. As shown in FIG. 8, once the implant14 is suitably positioned system 10 can be removed from the defect site.As described previously the implant 14E may expand to fill the defectsite.

In some situations, the length of the implant 14 may need adjustment. Ifthe implant material is too short and does not properly fill the defectsite then multiple implants may be inserted. As shown in FIG. 9, if theimplant is too long (e.g. a portion of the implant extends from thewound), the undesired portion of the implant 210 can be removed with asuitable trimming tool 212 (e.g. scalpel, scissors). It is alsoconceivable that the delivery system 10 may incorporate a cutting blade,knife or other tool at its distal end (not shown) for purposes ofreshaping the implant.

In some instances, the defect site may need to be modified to removenon-viable tissue or otherwise adjust the size of the defect. FIG. 10depicts a coring tool 110 that can be used both to remove a healthyharvest tissue plug for use at a defect site and to reshape a defectsite to allow for a better fit of a tissue implant. The coring tool 110has a generally cylindrical distal portion 140 and distal tip 130 bothof which are formed of a hardened stainless steel. The distal portion140 may have indicator markings 132 to help gauge the depth of the toolwith respect to the wound site during the coring process. The main bodyof the coring tool 138 has a proximal segment and may have a knurledportion 136 to provide the surgeon with a good gripping surface, and aproximal surface 134. The coring tool also includes a coring sleeve 142consisting of an elongated thin walled tube 143 with a cylindrical knob144 on the proximal end. The coring tool 110 and coring sleeve 142 areassembled as shown in FIG. 11 and hammered or otherwise inserted intothe wound site. With this tool, an irregular wound site 146 can beshaped into a more regular modified wound site 148 by removing portionsof the bone 150 from the wound site.

It is anticipated that the coring tool 110 may be available in a numberof sizes to address the variety of tissue defect configurations that maybe encountered. The tissue defect can be inspected eitherarthroscopically or directly and the size thereof can be measured. Theappropriate coring tool/delivery system 110 can be selected (e.g., 5, 6,7, 8, 9, 10 mm diameters on the distal core tool tip 140). These coringtools can be color-coded to correspond in size with the diameter of thedefect and with the implant sizes and delivery system. Using a sturdymallet, the coring tool 110 is then driven into the bone 152 to thedesired depth (e.g. 15 mm) and the core material 150 can be removed. Asdepicted in FIG. 9, when used properly the tool can be used to change anirregularly shaped defect site 146 into a more regularly sized implantsite 148.

The core tool inner sleeve 142 can be removed from the core tool body138 to provide a clear delivery path for the implant material into themodified wound site 148. The removed tissue or bone 150 is autologousmaterial and may contain active growth factors or other beneficialcomponents and as such may be further modified (e.g. ground-up) and usedfor insertion into this or other wounds, or incorporated into theimplant 14, to help stimulate healing.

The coring tool can also be used as a delivery instrument as shown inFIG. 13. In this alternative embodiment, the implant material can beloaded into the delivery system while the delivery system (e.g., coringtool 110) is pre-positioned at or within the defect site. Thus, as shownin FIG. 11, after the coring tool 110 has been inserted so that itsoutlet 130 (as shown in FIG. 10) is within the wound a pusher 154 can beextended or pushed down the central passageway 156 as describedheretofore so that its distal end portion 155 forces the implant 14towards outlet 130. After the implant is pushed to the end of thecentral passageway 156 by the pusher 154, the tubular body 138 is itselfwithdrawn from the wound 148 and moved completely outside the body ofthe patient. This action leaves the implant 14 within the wound.

It should also be readily apparent from the above description that morethan one implant device 14 could be used. For the tissue defecttreatment systems 10 and 110 and, if the physician were to decide to usemore than one plug, he/she need only remove plunger 22, insert a implant14 (of the same or different material) into the proximal end of lumen 19and then reinsert plunger 22 behind it. Alternatively, the entire system10 could be removed and replaced with a second one, which has beenpreloaded and is ready for immediate use. Thus, it will be appreciatedthat a second, third, etc., implant 14 may be delivered and applied tothe defect site or to multiple defect sites during a procedure. FIGS.14-16 describe another method for loading multiple implants 14 into thebody of a patient through an alternate delivery treatment system 162.FIG. 14 shows tissue defect treatment system 162 generally comprises asheath 12, and a mass of implant material 14.

It is further contemplated that multiple implants of variouscompositions may be delivered to the same site, or other nearby sites.The various compositions may be selected for any number of reasons,including but not limited to, the delivery of various therapies orvarious degrees or types of bio-matching (e.g., porous center or deepregion followed with a hard surface component/implant).

Sheath 12 generally comprises a tubular housing 18 defining a lumen 19,a hub 20 disposed at the proximal end of housing 18. In general, thetubular housing 18 has a window 158 formed in a portion of the wall ofthe tube for purpose of inserting implant devices 14. The size of thewindow is chosen so as to permit entrance of a variety of sizes of theimplant 14. The system uses an applicator (not shown in entirety)similar to applicator 16 in FIG. 1. The applicator basically comprisesan elongated, cylindrical rod-like plunger 22 having a thumb plate (notshown) disposed at its proximal end and a distal end 15. To load implant14 into the device, plunger 22 is retracted until the distal portion 15is proximal to the window 158 in tubular housing 18 and indicator marks250 on plunger 22 are visible as shown in FIG. 15. Plunger 22 is thenadvanced and implant 14 is transferred through the sheath 18 to thetarget site. Another plug 14B could be loaded and positioned into window158, as shown in FIG. 14, and then directed toward the same or anothertissue defect site. This system may have particular advantages during anendoscopic procedure where the physician does not want to remove thedelivery system from the patient to deliver additional plugs, such plugsmay be of different composition 14C. With system 162 the sheath 12remains within the patient and additional implants can be loaded intothe device.

It is also conceivable that a cartridge or magazine of implants, similarto is used for delivering surgical staples, could be attached to thedelivery system to provide automated or semi-automated loading of one ormore implants. The cartridge could be designed to interface with window158 or cartridges could be designed to connect directly to the distalportion of applicator 16 as shown in FIG. 17-19. Treatment system 200,shown in FIG. 17 is similar to treatment system 10 of FIG. 1 except thatit can be used in conjunction with the implant carrying cartridges 202and 204 shown in FIGS. 18-21. The cartridges are essentially thin walledcylindrical tubular structures designed to store implant devices. Thecartridges can be fabricated from thin walled stainless steel orinjection molded polymers such as polycarbonate. The cartridges 202 and204 can be sized to hold implants of various outer diameters andlengths. By way of example, cartridge 202 can accommodate large diameterimplant 206 and cartridge 204 can accommodate small diameter implant208. The cartridges are designed to attach to the distal portion 216 oftreatment system 200. The proximal segment of cartridges 202 and 204 hasan attachment portion 218A and 218B that connects to the distal portion216 of the treatment system. The attachment can be by way of a taperedinterference fit, screw thread, bayonet attachment, dimpled attachmentring or any other [means] know to those skilled in the art. The size andlength of the desired implant and related cartridge can be selected bythe surgeon and attached to the treatment system. The distal portion ofthe cartridge 220A and 220B is positioned at the desired site and thethumbplate 24 can be depressed to advance the distal end 15 of theapplicator 16 into contact with the implants 206 and 208 to eject theimplants from the cartridge sleeves 202 and 204. Once the implant isejected, the empty cartridge sleeve 202 or 204 can be removed andreplaced with another cartridge.

The design of treatment system 200 allows one delivery system to be usedto delivery one or more similar or different sized implants.

Additionally, these embodiments may be used to deliver a plurality offlowable implants, wherein indicator markings 250 may be used to measurethe amount of each implant. Likewise, the coring tool 110 may be used toremove material to a certain depth, or a measured depth, as indicated bycore depth indications 154. The amount of implant material 14 necessaryto fill the voids or defects may be calculated or determined bycorrelating coring indication markings 145 with plunger markings 250.This correlation may be performed whether the coring tool 110 is usedseparately from the system 10, or whether the plunger mechanism 22 isfed through the core tool body 138 (i.e., whether two instruments areused, or both steps are performed through the single tool, as previouslydiscussed) as previously described.

FIG. 22 depicts a 100× Scanning Electron Microscope image of anembodiment of a bone replacement material. This implant is composed ofKensey Nash P1076, a bovine hide-derived collagen material that is acombination of native collagen fibers and soluble collagen. The porescomprising the macrostructure of the implant are between 100-um and200-um in diameter.

FIG. 23 depicts a 100× Scanning Electron Microscope image of a bonereplacement material. A constituent of this implant is Kensey NashP1076, a bovine hide-derived collagen material that is a combination ofnative collagen fibers and soluble collagen. Blended into the collagenat 25% by weight is medical grade calcium sulfate, shown as the smallcylindrical particles throughout the porous macrostructure.

FIG. 24 depicts a 100× Scanning Electron Microscope image of anembodiment of a bone replacement material. This implant is composed ofKensey Nash P1076, a bovine hide-derived collagen material that is acombination of native collagen fibers and soluble collagen. This implanthas been crushed by approximately 233% causing the pore size to decreaseto 20-um to 50-um, thereby imparting a bio-matched condition, morespecifically, a porosity matched or compliance matched condition.

As described previously, the implant can be used to deliver a variety ofagents (e.g., drugs, biologics, etc.) into the patient's body. FIG. 25depicts agent elution 164 from implant 14A. In this embodiment, theimplant may be constructed to effect an immediate or time-phaseddelivery of one or more active ingredients. The presence of the implantand delivery of selected agents is designed lead to improvements inpatients with tissue defects through at least one of several methodssuch as: (1) an agent or biologic can act as a signaling molecule toactivate a proliferating or differentiating pathway, (2) an agent mayact as a depot for nutrients for proliferating and growing cells, and(3) an agent may prevent an adverse tissue response to the implant.

In the preferred embodiment shown in FIG. 25, agent delivering implantmaterial 14A, the device provides continuous smooth release of theactive agent 164 over all or some of the degradation period of thedevice. In another preferred embodiment, the agent is released at alltimes during which the device remains in the tissue. In certainapplications it may be necessary to provide one or more burst releasesof the active agent. The device may also be designed to deliver morethan one agent at differing or staged intervals and dosages. It is alsoconceivable that the implant 14A may be designed to hold the agentwithin the boundary of the device (e.g. not release the agent tosurrounding tissues) so as to affect only those cells that migrate intothe porous structure of the device.

As a non-limiting example, implant 14A could incorporate microparticleswithin its structural framework. The particles degrade afterimplantation in the body of a living being and can be used to deliverany type of molecular compound, such as proteins, genetic materials,peptides, pharmacological materials, vitamins, sedatives, steroids,hypnotics, antibiotics, chemotherapeutic agents, prostaglandins, andradiopharmaceuticals. The delivery system of the present invention issuitable for delivery of the above materials and others, including butnot limited to proteins, peptides, nucleotides, carbohydrates, simplesugars, steroids, pharmaceuticals, cells, genes, anti-thrombotics,anti-metabolics, growth factor inhibitor, growth promoters,anticoagulants, antimitotics, and antibiotics, fibrinolytic,anti-inflammatory steroids, and monoclonal antibodies. Microspheres canbe made of a variety of materials such as polymers, silicone and metals.Biodegradable polymers are ideal for use in creating microspheres.Several variables can influence the mechanism and kinetics of polymerdegradation, for example, material properties like crystallinity,molecular weight, additives, polymer surface morphology, andenvironmental conditions. As such, to the extent that each of thesecharacteristics can be adjusted or modified, the performance of thisinvention can be altered.

After the implants of this invention are positioned within the structureof the body of the living being, the portions of the device will degradeor resorb as new cells and tissue migrate into the implant. FIG. 26depicts the tissue defect site and implant over time. Implant 171 isshown at an early time point right after implantation, implant 172 isshown at some later time point, implant 173 at yet a later time point,and implant 174 is shown at a fourth time point at which the implant isnearly completely resorbed and replaced by healthy tissue 170.

FIG. 27 depicts a magnified view of a portion of yet another embodimentof the implant device 230 that is comprised of a series of sphericallike structures or beads 232 that are connected together to form amacrostructure or framework for the implant device 230. The beads 232can be made from a variety of materials such as calcium alginate,polylactic acid, gelatin or any other suitable biomaterial describedherein or known to those skilled in the art. This particular embodimentmay also incorporate native collagen fibers 234 and a filling material236. The filling material can be a made from a more soluble collagensuch as Semed S manufactured by Kensey Nash Corporation of Exton, Pa. oranother biomaterial known to those skilled in the art.

FIG. 28 depicts yet another embodiment of the implant material, implant240, that includes an anchoring element 244. The anchoring element canbe used to hold implant 240 in the defect site during the healing of thedefect.

FIG. 29 depicts an embodiment of an agent delivery system (e.g. syringe)that is actively loading implant 14 with an agent (e.g. bone marrowcells, growth factors, antibiotics, etc.). In this embodiment, the agent262 is drip-loaded into the implant 14 prior to placement within adelivery system and hence prior to implantation in the living being. Thedelivery system 260 comprises a syringe-like body 270, which containsthe agent 262. The agent plunger 264 is advanced in the direction of thearrow to dispense the agent from the distal exit orifice 268 of thesystem 260. A preset quantity of agent can be applied to the implant orsurrounding tissue depending upon the application. Markings (not shown)can be used to measure the amount of agent applied. It is also conceivedthat the implant could be loaded with an agent while stored within adelivery system and also loaded with the agent after the implant ispositioned into the tissue of the living being.

FIG. 30 is a side view in partial cross-section of a portion of adelivery system applying yet another embodiment of an implant of thesubject invention. This segmented implant delivery system 280 issuitable for delivery of implants 282 that are comprised of multiplesegments (e.g. granules, chips, fibers, etc.). These implants may bemore suitable for filling non-uniform or irregular tissue defects 286 intissue of a living being 30. The syringe-like delivery system utilizes acylindrical housing body 270 to hold the material and a plunger 264 toeject the material from the distal opening of the syringe body. Thesegmented implant can flow or be otherwise distributed to fill the void.The implant material can be of any material or combination of materialspreviously described herein.

Numerous other embodiments and modifications will be apparent to thoseskilled in the art and it will be appreciated that the above descriptionof a preferred embodiment is illustrative only. It is not intended tolimit the scope of the present invention, which is defined by thefollowing claims. Without further elaboration the foregoing will sofully illustrate our invention that others may, by applying current orfuture knowledge, adopt the same for use under various conditions ofservice.

1. An implant for the repair or regeneration of bone, said implantcomprising at least a first portion and a second portion, said firstportion comprising a sleeve material and said second portion comprisingan inner core material, with at least a portion of said implantcomprising native insoluble collagen.
 2. The implant of claim 1 whereinsaid inner core material comprises calcium salt.
 3. The implant of claim2 wherein said calcium salt comprises at least one of calcium phosphateand calcium sulfate.
 4. The implant of claim 1 wherein at least aportion of said sleeve material comprises said native insolublecollagen.
 5. The implant of claim 1 wherein said sleeve material ishemostatic.
 6. The implant of claim 1 wherein said first portion andsaid second portion are resorbable, with said first portion resorbingfaster than said second portion.
 7. The implant of claim 6 wherein saidinner core material provides structural integrity to said implant. 8.The implant of claim 7 wherein said inner core material comprises atleast one of calcium phosphate and calcium sulfate.
 9. The implant ofclaim 8 wherein said implant is hydrated with autologous blood.
 10. Theimplant of claim 1, wherein at least a portion of said sleeve materialcomprises metal with said sleeve material serving as a scaffold.
 11. Theimplant of claim 1, wherein at least a portion of said sleeve materialcomprises metal.
 12. The implant of claim 1, wherein said inner corematerial additionally comprises soluble collagen.